Structure-activity relationship study of a series of caspase inhibitors containing γ-amino acid moiety for treatment of cholestatic liver disease. Issue 10 (1st June 2018)

• Record Type: Journal Article
• Authors: Mou, Jianfeng; Wu, Songliang; Luo, Zhi; Guo, Fengying; He, Haiying; Wang, Jianhua; Lin, Fusen; Guo, Fengxun; Sun, Jianping; Shen, Liang; Zeng, Minggao; Wang, Chuan; Xu, Deming; Gu, Zhengxian; Tian, Xin; Zhang, Aiming; Xu, Hongjiang; Yang, Ling; Zhang, Xiquan; Li, Jian; Chen, Shuhui
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 28:Issue 10(2018)
• Page Start: 1874
• Page End: 1878
• Publication Date: 2018-06-01
• Subjects: Apoptosis -- Caspase inhibitor -- γ-Amino acid -- Chronic liver disease; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2018.04.002
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Highlights: A series of caspase inhibitors containing γ-amino acid moiety have been synthesized. Several derivatives showed promising efficacy in cell-based Jurkat/Fas (JFas) assays. Compound 20o demonstrated ameliorating total bilirubin efficacy in an ANIT cholestatic model. Abstract: A series of caspase inhibitors containing γ-amino acid moiety have been synthesized. A systemic study on their structure-activity relationship of anti-apoptotic cellular activity is presented. These efforts led to the discovery of compound 20o as a potent caspase inhibitor, which demonstrated preclinical ameliorating total bilirubin efficacy with a significantly improved pharmacokinetic profile.